Introduction

In 2013, the New York Times called kidney disease "an underestimated killer," because it kills more Americans (90,000 every year) than cancers of the breast and prostate combined.

The kidneys are a pair of fist-sized organs located on either side of the spinal column. Kidneys perform life-sustaining functions that keep the rest of the body in balance in a number of ways.

They remove waste products, including salt, and excess fluids that build up in the body. They help maintain a safe level of blood chemicals in the body, such as potassium, sodium, and chloride, and they control blood pressure.

Early kidney disease has few symptoms. As it worsens, complications such as high blood pressure, arteriosclerosis (the thickening and hardening of the walls of the arteries), anemia, weak bones, and nerve damage can develop. If the disease progresses to kidney failure, dialysis or a kidney transplant is needed.

Some forms of kidney failure are temporary and may get better. This is called acute kidney failure. Chronic or end-stage kidney failure is the result of an irreversible scarring process that results in the shutdown of the kidneys.

Chronic kidney failure does not get better. Veterans with chronic kidney failure need dialysis treatments for the rest of their lives, or may receive a kidney transplant if they are medically eligible.

New, Ongoing, and Published Research

VA has a comprehensive research portfolio aimed at preventing and improving the treatment of chronic kidney disease. There are many causes of chronic kidney disease, but the two main causes—accounting for up to two-thirds of all cases—are diabetes and high blood pressure.

In 2012, VA and the University of Michigan began the work of creating a national kidney disease registry to monitor kidney disease among Veterans. The registry will provide accurate and timely information about the burden and trends related to kidney disease among Veterans and identify Veterans at risk for kidney disease.

VA hopes the kidney disease registry will lead to improvements in access to care, such as kidney transplants. The department also expects the registry will allow VA clinicians to better monitor and prevent kidney disease, and will reduce costs related to kidney disease.

➤ Work of Dr. Thomas Starzl

Dr. Thomas E. Starzl, who passed away in 2017 at age 90, was a VA transplant surgeon and research scientist for more than 50 years. He began his VA career in the 1950s as a resident surgeon in the Chicago VA Medical Center, and went on to serve at the Denver and later the Pittsburgh VA medical centers.

In 1962, while on the staff of the Denver VA Medical Center and the faculty of the University of Colorado Medical Center, Starzl conducted the first in a series of kidney transplants that consistently resulted in long-term survival for patients. He used the immunosuppressant drug azathioprine and the steroid prednisone to keep the body from rejecting the new kidney. While he was not the first surgeon to perform a successful kidney transplant—that accolade goes to Harvard's Dr. Joseph Murray, whose patient from a 1954 procedure would go on to live eight years following the operation—Starzl is credited with the "first-ever series of repetitively successful human kidney transplantations."

Widely regarded as the "father of transplantation," Starzl is also credited with performing the first successful liver transplant, on May 5, 1963. No patient had survived the operation previously. While Starzl's patient did succumb to pneumonia weeks after the transplant, it was still considered a groundbreaking success and did pave the way for life-saving procedures for many others in the years to come.

Starzl spent much of his research career working on anti-rejection medications that would markedly increase transplant survival rates. In 2011, he received the Lasker-DeBakey Clinical Medical Research Award, one of the most respected science prizes in the world, for his career accomplishments. As of 2017, he was one of seven VA researchers to have earned the honor.

➤ Erythropoietin

The drug erythropoietin (EPO) is used to treat anemia, a shortage of red blood cells common in patients with kidney failure. In 2002, a team of researchers led by Dr. Denise Hynes of the Edward Hines Jr. VA Hospital in Chicago found that by injecting the drug under the skin instead of into a vein, they could use smaller amounts of this very effective, but expensive, medication.

In 2011, the Centers for Medicare and Medicaid Services (CMS) changed their billing procedures to enable physicians to bill Medicare and Medicaid in such a way as to reflect the significant cost-savings achieved by administering smaller amounts of the drug. Thus, this VA study directly translated into savings for taxpayers.

➤ Acute kidney injury

AKI, once called acute renal failure (ARF), is an abrupt loss of kidney function that develops within 48 hours. Disease, some antibiotics, crushing injuries (including blast injuries), and other issues can cause AKI.

High-intensity vs. low-intensity treatment—In 2008, a VA/National Institutes of Health research team looked at whether high intensity treatment (undergoing dialysis six times a week instead of three times a week and at higher filtration rates) was better for critically ill patients with AKI than less intensive treatment (undergoing dialysis three times a week at lower filtration rates).

They found that intensive support did not decrease death rates, improve the recovery of kidney function, or reduce the rate of failure of other organs, compared with the less-intensive therapy.

Tool for predicting likelihood of AKI—AKI often occurs after surgeons conduct two procedures that are used to diagnose and treat cardiovascular conditions: cardiac catheterization and percutaneous coronary intervention.

A 2015 study by VA researchers throughout the nation, led by a White River Junction (Vermont) VA Medical Center investigator, developed a tool for predicting the likelihood that AKI will develop in patients undergoing either or both of those procedures.

After reviewing more than 115,000 such procedures, the researchers developed a clinical prediction model that can automatically identify patients at high risk of developing AKI both before and after the procedures are performed. The researchers are now working to incorporate this model into VA's routine clinical practice.

Patients with AKI at risk for CKD—Another 2015 study, by researchers from the VA Ann Arbor Healthcare System, the University of Michigan, and the Centers for Disease Control and Prevention, found that patients who developed AKI while hospitalized for any reason were at substantial risk of developing CKD (see below) within one year of their hospitalization.

In addition, the team found that those patients who took 10 or more days to recover from AKI were at high risk of developing CKD, even if their AKI was a mild form of the disease.

➤ Chronic kidney disease

The kidneys remove waste products and extra fluid and flush them from the body as urine. When they are not working properly, wastes build up in the blood. A diagnosis of CKD means that the patient's kidneys have not been working properly for some time.

Relationship between CKD and other diseases—In 2015, a team of researchers from the Richmond, Virgina, and Buffalo, New York, VA medical centers published a study of the relationship between CKD and other diseases. In reviewing the records of 75,787 Veterans who visited a VA outpatient clinic at least once during 2007, they found that 47.3 percent had CKD—a much higher percentage than would be expected in the general population.

They also found that patients with CKD were more likely to have vascular disease, diabetes, hypertension, and cancer than those who did not. They argued that finding ways to recognize CKD earlier in patients and to modify the risks of the disease is an important public health priority.

Statin use associated with AKI and CKD—Another 2015 study, by researchers from the VA Central California Health Care System; VA North Texas Health Care System; University of California, San Francisco; and University of Texas Southwestern Health Care System, found that statin use is associated with both AKI and CKD. As part of the analysis, the team analyzed data from 6,342 statin users and 6,342 non-users—who were matched to the users on the basis of 82 health and demographic factors—from among patients in the San Antonio area military health care system from 2003 through 2012.

The study found that the statin users had higher odds of developing AKI and other kidney diseases, including nephritis, nephrosis, and renal sclerosis. The risk was higher in patients taking high-intensity statins compared with those on low-to-moderate intensity statins.

The findings suggested that the long-term effects of statins in real-life patients may differ from shorter-term effects in selected clinical-trial populations. However, the authors stressed that the study is not conclusive and was not designed to address whether the drugs' possible kidney risks outweigh their proven cardiovascular benefits. They recommended further research.

➤ Restless legs syndrome and sleep apnea

Restless legs syndrome and kidney disease—Restless legs syndrome (RLS) is a disorder in which people lie down and attempt to rest, but then feel an uncontrollable urge to keep moving their legs. It affects as many as 1 in 10 Americans. Those with severe RLS have great difficulties sleeping because they toss and turn constantly or get up and pace the floor.

A study published in 2015 by a team of researchers from the Memphis VA Medical Center, the University of Tennessee Health Science Center, and the University of California, Irvine, looked at 3,700 Veterans with new diagnoses of RLS. They found that these Veterans had kidney disease three times as often as other Veterans with the same demographic characteristics—and had heart disease and strokes four times as often.

The study did not show that RLS brought on the other conditions, but only that there was an association. It is possible that RLS is a result of kidney disease, heart disease, or stroke.

Sleep apnea and kidney disease—Another disorder related to sleep, sleep apnea, was associated with a greater risk of kidney disease in a 2015 database study of more than 3 million VA patients. In obstructive sleep apnea, the airway becomes narrowed or blocked during sleep.

Researchers from the same facilities as the RLS study also found that Veterans with sleep apnea were at greater risk of coronary heart disease, strokes and death from any cause. Like the RLS study, the researchers did not show that sleep apnea caused kidney disease and the other outcomes—only that there was a strong relationship between them.

➤ Kidney disease and health disparities

Kidney transplants within VA—Living donor kidney transplantation has the best outcomes in terms of survival and is the most cost-effective treatment for patients with end-stage renal disease (ESRD), the last stage of chronic kidney disease and the time when dialysis or transplant is needed to stay alive. A 2007 study found that ESRD patients who receive health care from VA were 35 percent less likely to get a kidney transplant than privately insured patients.

In addition, minority patients within VA were less likely to get a transplant than whites. While the incidence of ESRD in African Americans is four times higher than in Caucasians in the United States, African Americans are less than half as likely to be referred for or to undergo kidney transplants.

Fewer transplants in African Americans—A 2015 study by researchers from the Ralph H. Johnson VA Medical Center in Charleston and the Medical University of South Carolina asked 27 African American kidney recipients about their perspectives on the challengers, barriers, and educational needs related to kidney transplants from living donors.

According to those surveyed, reasons that African Americans seek and receive fewer transplants include concerns for the donor; a general lack of knowledge about the process, including risks, the cost of surgery, and the impact on both the donor and the recipients' future health; and the difficulty of approaching potential donors.

Participants thought that an educational program led by an African American recipient of a kidney from a living donor, including guidance on how to approach others to ask if they might be willing to donate, would increase the number of transplant-eligible patients looking for kidney transplants from living donors.

One CSP trial involves angiograms. An angiogram is an X-ray image of the blood vessels. A special dye used in some angiograms to allow doctors to visualize blocked blood vessels can cause problems in some individuals, especially the elderly and those with diabetes, chronic kidney disease, or advanced heart failure.

These problems can include the need for dialysis, prolonged hospitalization, a worsening of chronic kidney disease, and even death. CSP 578, titled "Prevention of serious adverse events following angiography (PRESERVE)," will compare the effectiveness of three different drugs (isotonic sodium bicarbonate, intravenous isotonic sodium chloride, and oral N-acetylcysteine) and a placebo, to see which of these medications, if any, may be able to reduce patients' risk of developing these complications.

Researchers in a second CSP study (CSP 565, the VA NEPHRON-D: Nephropathy in

Diabetes study) assessed a new therapy that may decrease the progression of diabetic kidney disease. They stopped the trial before it was scheduled to end because the therapy increased the risk for serious adverse effects in patients with diabetic nephropathy, or damage to the kidneys caused by diabetes. (Diabetes is the leading cause of ESRD in the United States.)

The researchers were assessing a combination therapy using two different drugs that block the renin angiotensin system, a signaling pathway responsible for regulating blood pressure. The two drugs are angiotensin receptor blockers and angiotensin-converting enzyme inhibitors.

They found that the combination therapy increased the risk of hyperkalemia, which is higher than normal levels of potassium in the blood. It also increased levels of AKI in study participants.

In a paper published in the New England Journal of Medicine in 2013, the study's researchers concluded that the risks of the therapy outweighed its possible benefits. They therefore stopped the study.

In 2015, the NEPHRON-D team found that in 1,448 patients with proteinuric diabetic kidney disease, a mean systolic blood pressure greater than 140 mm HG and a mean diastolic blood pressure greater than 80 mm Hg were associated with a greater tendency to progress to ESRD.

The researchers found that while control of patients' blood pressure delays the progression from kidney disease to ESRD, the optimal blood pressure to improve outcomes was still unclear.

A third CSP study, completed in 2007, found that patients with ESRD treated with high doses of folic acid and B vitamins did not survive longer or have fewer cardiovascular problems than those who did not receive the treatment.

➤ Risk of kidney disease from some colonoscopy prep agents

A study that examined the records of more than 70,000 Veterans over age 50 found that the use of sodium phosphate enemas—a common method of cleansing the bowel in preparation for colonoscopy—increases the risk of long-term kidney injury. The researchers, based at the Kansas City (Mo.) VA Medical Center, discovered that the use of sodium phosphate enemas versus polyethylene glycol (PEG) prior to colonoscopy is associated with a 38 percent increase in the chance of developing a decline in kidney function one year following the exposure. As such, the study team recommended that the use of sodium phosphate enemas be limited.

Sodium phosphate enemas have been used both to treat constipation and to enhance bowel preparation for procedures. The enema contains sodium and phosphate and acts by pulling water into the gastrointestinal tract.